We have previously shown that TGF? signaling is a key regulator of the tendon cell fate: TGF? signaling is a potent inducer of tendon markers and disruption of TGF? signaling in limb bud mesenchyme resulted in failure of tendon development. This proposal is based on observations regarding the role of TGF? signaling in later stages of tendon development. We find that disrupting the type 2 TGF? receptor (T?R2) in tenocytes using the ScxCre tendon deletor resulted in tendon degeneration in early postnatal stages. Interestingly, embryonic development of the tendons was not affected and the tendons developed a robust and organized collagen matrix, but in early stages of postnatal development the movement of T?R2;ScxCre pups was perturbed and their tendons showed gradual loss of tendon markers followed by degenerative processes. Moreover, we find that tenocyte dedifferentiation was not due to an intrinsic loss of TGF? signaling, since loss of the T?R2 in isolated patches of tenocytes did not have a similar effect. We therefore hypothesize that loss of TGF? signaling results in disruptions to cell-cell or cell-matrix interactions in tendons leading o tenocyte dedifferentiation and tendon degeneration. The proposed project follows these observations in three major directions, the first aim is to determine if there is a developmental time window in which disruption of TGF? signaling will lead to tendon degeneration and to develop more limited model of the phenotype that will enable following the full scope of the degenerative process and developing it as a system for analysis of tendinopathy. In the second aim we will investigate the cellular and molecular changes in the mutant tendons to identify the key features essential for maintenance of the tendon cell fate. Finally, in the third aim we analyze the role of activin signaling in this process based on preliminary results that show synergistic interactions between TGF? and activin signaling.